5,6-dihydroimidazo(2,1-b)thiazole-2-carboxamide derivatives or salts thereof

ABSTRACT

5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivatives represented by the following general formula [I]    &lt;IMAGE&gt; (I) wherein R1, R2, R3 and R4 are either the same or different and mean individually a hydrogen atom or lower alkyl group, Y denotes a specific phenyl-containing substituted amino group, and their salts. These compounds have excellent immuno-modulating activities.

This is a continuation-in-part of U.S. Ser. No. 853,204 filed on Apr. 17, 1986.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivatives, and more specifically to 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivatives having excellent immuno-modulating activities.

2. Description of the Prior Art

A number of compounds having the imidazothiazole skeleton have heretofore been synthesized. For example, an imidazo[2,1-b]thiazole derivative (levamisole) represented by the following formula: ##STR2## has been reported to have some immuno-modulating activities (German Offenlegungsschrift No. 23 40 632).

It has also been reported that certain anti-inflammatory activities are exhibited by imidazo[2,1-b]thiazole derivatives represented by the following formula: ##STR3## wherein R₁₀ means a C₁ -C₃ -alkylsulfonyl or ##STR4## group, R₁₄ and R₁₅ being independently a hydrogen atom or a monofluorophenyl, trifluoromethylphenyl or trimethylphenyl group with a proviso that when either one of R₁₄ and R₁₅ is a hydrogen atom the other one is other than a hydrogen atom or being coupled to each other together with the associated nitrogen atom to form a 1-(2,3-dimethyl)pyrrolidinyl group, R₁₁ denotes a C₁ -C₃ -alkyl or phenyl group, and R₁₂ and R₁₃ stand independently for a hydrogen atom or a C₁ -C₄ -alkyl group [U.S. Pat. No. 4,224,334; J. Med. Chem. 24, 604-609 (1981)]; and by 5,6-dihydroimidazo[2,1-b]-thiazole derivatives represented by the following formula: ##STR5## wherein R₁₆ means a substituted or unsubstituted phenyl or naphthalyl group (Japanese Patent Laid-Open No. 169490/1982).

SUMMARY OF THE INVENTION

An object of this invention is to provide certain imidazo[2,1-b]thiazole derivatives having excellent immuno-modulating activities.

With the foregoing in view, the present inventors synthesized a variety of imidazo[2,1-b]thiazole derivatives and their physiological activities were investigated. As a result, it has been found that novel 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivatives having certain specific substituents and represented by the above general formula (I) have excellent immuno-modulating activities, leading to completion of this invention.

In one aspect of this invention, there is thus provided a 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivative represented by the following general formula [I] ##STR6## wherein R₁, R₂, R₃ and R₄ are either the same or different and mean individually a hydrogen atom or lower alkyl group, Y denotes a group of the following formula: ##STR7## wherein R₅ means a lower alkyl group, X denotes a hydrogen or halogen atom or a trifluoromethyl, lower alkyl, lower alkoxy or nitro group, n stands for an integer of 0-5, and when n is greater than 1, Xs are either the same or different; ##STR8## wherein A means a lower alkylene group which may be branched, R₆ denotes a hydrogen atom or a lower alkyl or cycloalkyl group, and X and n have the same meaning as defined above; ##STR9## wherein R₇ means a hydrogen, chlorine, bromine or iodine atom or a lower alkyl, lower alkoxy or nitro group; or ##STR10## wherein R₈ means a halogen atom or a lower alkoxy or trifluoromethyl group and R₉ denotes a halogen atom or a hydroxyl, lower alkoxy or trifluoromethyl group), with a proviso that at least one of R₁, R₂, R₃ and R₄ is a methyl group when the group Y is ##STR11## or a salt thereof.

As salts of the 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivatives in the present invention, may be mentioned their pharmacologically acceptable salts, for example, their inorganic and organic acid salts such as hydrochlorides, sulfates, carbonates, nitrates, hydrobromides, phosphates, sulfonates, acetates, oxalates, tartrates, citrates, malates, glutamates, aspartates, etc.

The compounds (I) of this invention and their salts may contain water of crystallization. Their hydrates are all embraced within the scope of this invention.

The compounds (I) of this invention and their salts have excellent immuno-modulating activities and can hence be used, as preventive and therapeutic medicines for immunological disease, for the treatment and prevention of autoimmune diseases such as chronic rheumatoid arthritis, systemic lupus erythematodes, collagen disease, chronic nephritis and autoimmunohemolytic anemia, delayed-type and immediate-type allergic diseases, malignant tumors and serious infectious diseases by way of example.

The above and other objects, features and advantages of this invention will become apparent from the following description and the appended claims.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

The compounds (I) of this invention may be roughly divided into the following three groups (Ia)-(Ic): ##STR12## wherein Z means a group of the following formula: ##STR13## wherein R₇ means a hydrogen, chlorine, bromine or iodine atom or a lower alkyl, lower alkoxy or nitro group; or ##STR14## wherein R₈ means a halogen atom or a lower alkoxy or trifluoromethyl group and R₉ denotes a halogen atom or a hydroxyl, lower alkoxy or trifluoromethyl group; and and R₁ -R₆, A, X and n have the same meaning as defined above.

The term "lower" as used herein such as "lower alkylene", "lower alkoxy" and the like means 1-5 carbon atoms.

Among the compounds (Ia), those represented by the following formula (Ia-1) are preferred: ##STR15## wherein m stands for an integer of 1-3, and R₁, R₃, R₄, R₆, X and n have the same meaning as defined above.

Of the compounds (Ia-1), particularly-preferred compounds are those having the formula (Ia-1) in which R₁, R₃, R₄ and R₆ mean individually a hydrogen atom or methyl group and X denotes a halogen atom or trifluoromethyl group.

Among the compounds (Ia-1), still preferred compounds are represented by the following formulae respectively. ##STR16## wherein R₁₉ means a hydrogen atom or alkyl group having 1-3 carbon atoms, m stands for an integer of 1-3, and X and n have the same meaning as defined above.

Among the compounds (Ib), those represented by the following formula (Ib-1) are preferred: ##STR17## wherein R₁₇ and R₁₈ may be either the same or different and mean individually a hydrogen, chlorine or iodine atom or trifluoromethyl group, with a proviso that R₁₈ is other than a trifluoromethyl group when R₁₇ is a hydrogen atom, and R₁ and R₃ have the same meaning as defined above. Of these, those represented by the formula (Ib-1) in which R₁ and R₃ are individually a hydrogen atom or methyl group are especially preferred.

Among the compounds (Ic), those represented by the following formula (Ic-1) are preferred: ##STR18## wherein R₃, R₄, R₅, X and n have the same meaning as defined above. Of these, particularly-preferred compounds are those represented by the formula (Ic-1) in which R₃ and R₄ are individually a hydrogen atom or methyl group, R₅ denotes a methyl or ethyl group, and X stands for a halogen atom or trifluoromethyl group.

The compounds (I) of this invention can each be prepared, for example, by reacting an imidazolidine-2-thione represented by the following formula (III) with an amide represented by the following formula (II) in accordance with the following reaction formula: ##STR19## wherein R₁, R₂, R₃, R₄ and Y have the same meaning as defined above.

It is preferable to conduct the above reaction in a suitable inert solvent. As an illustrative solvent useful in the above reaction, may be mentioned benzene, toluene, xylene, acetone, methyl ethyl ketone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, ethyl ether, tetrahydrofuran, dioxane, chloroform, water or the like.

The reaction temperature may be -5° C.-+100° C. or preferably +20° C.-+80° C. By proceeding with the reaction for 1-6 hours, the compound of this invention can be obtained with high yield and high purity.

In order to obtain the corresponding compound of the general formula (I) in its free form from the thus-obtained hydrochloride, it is necessary to treat the hydrochloride with a base, for example, an inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate or ammonia or an organic base such as pyridine or triethylamine. In order to derive other salts, it is required to treat the free compound with corresponding acids, for example, sulfuric acid, carbonic acid, nitric acid, hydrobromic acid, phosphoric acid, sulfonic acid, acetic acid, oxalic acid, tartaric acid, citric acid, malic acid, glutamic acid, aspartic acid and/or the like.

The compound of the formula (II), which is employed as a raw material in the above process, can be prepared, for example, in accordance with the following reaction scheme, namely, by reacting an amine (V) with a diketene (IV) to obtain a compound (VI) and then chlorinating the compound (VI) with sulfuryl chloride [Chemical Abstracts, 19, 43 (1925)], N-chlorosuccinimide or the like. ##STR20## wherein Y has the same meaning as defined above.

The other raw material (III) can be prepared, for example, in the following manner base on the process described in Org. Synth. Coll. 3, 394; ##STR21##

When the group represented by Y is ##STR22## in the compounds (I) of this invention obtained in the above manner, the following specific groups may be mentioned as preferred examples of these groups: ##STR23##

When Y stands for any one of the above exemplified groups, at least one of R₁, R₂, R₃ and R₄ means a methyl group. The methyl group is substituted to the 5- or 6-position of the imidazothiazole skeleton. The 6-substituted compound is preferred.

[EFFECTS]

Pharmacological effects of the compounds (I) of this invention and their salts will next be described.

Test 1

Effect on anti-SRBC PFC response in vitro:

In an RPMI-1640 culture medium containing 10% of fetal calf serum (FCS), 1×10⁷ spleen cells of BALB/c mouse were cultured together with sheep erythrocytes (1×10⁶) and a sample compound (0.2 or 1 μg/ml) for 5 days in a CO₂ incubator (37° C.) in accordance with the method reported by Mischell, R. I. et al. in J. Exp. Med. 126, 423 (1967) (with some modifications). The number of resultant plaque forming cells was counted by the method proposed by Jerne and Nordin [Science 140, 405 (1963)]. Results are shown in Table 1-A-Table 1-E.

                  TABLE 1-A                                                        ______________________________________                                          ##STR24##                    (Ia)                                                                                        Immune                                                                         response                                                                       potentiation                        Sample                                     activities                          compound                                   (Control =                          (1 μg/ml)                                                                           R.sub.1                                                                              R.sub.2                                                                              R.sub.3                                                                             R.sub.4                                                                             R.sub.5                                                                             X.sub.n 100%)                               ______________________________________                                         Comp'd 1                                                                               H     H     H    H    CH.sub.3                                                                            3,4-Cl.sub.2                                                                           377                                 Comp'd 30                                                                              H     H     CH.sub.3                                                                            CH.sub.3                                                                            CH.sub.3                                                                            3-CF.sub.3                                                                             271                                 Comp'd 31                                                                              H     H     CH.sub.3                                                                            CH.sub.3                                                                            CH.sub.3                                                                            3,4-Cl.sub.2                                                                           201                                 Comp'd 32                                                                              H     H     CH.sub.3                                                                            CH.sub. 3                                                                           CH.sub.3                                                                            3,5-(CF.sub.3).sub.2                                                                   199                                 Comp'd 3                                                                               H     H     CH.sub.3                                                                            CH.sub.3                                                                            CH.sub.3                                                                            4-CF.sub.3                                                                             203                                 Comp'd 2                                                                               H     H     CH.sub.3                                                                            CH.sub.3                                                                            CH.sub.3                                                                            3,5-Cl.sub.2                                                                           293                                 Comp'd 4                                                                               H     H     CH.sub.3                                                                            CH.sub.3                                                                            C.sub.2 H.sub.5                                                                     3,4-Cl.sub.3                                                                           177                                 ______________________________________                                    

                                      TABLE 1-B                                    __________________________________________________________________________      ##STR25##                                (Ib)                                                                Immune repsonse                                                                potentiation activities                                                        (Control = 100%)                                Sample compound                                                                          R.sub.1                                                                            R.sub.3                                                                            R.sub.4                                                                            R.sub.6                                                                            X.sub.n                                                                             0.2 μg/ml                                                                          1 μg/ml                               __________________________________________________________________________     Comp'd 45 H   H   H   H   4-Cl 252    302                                      Comp'd 55 H   H   H   H   2,4-Cl.sub.2                                                                        183    --                                       Comp'd 56 H   H   H   H   3,4-Cl.sub.2                                                                        239    --                                       Comp'd 60 H   H   H   H   3,5-Cl.sub.2                                                                        --     190                                      Comp'd 51 H   H   H   CH.sub.3                                                                           2,4-Cl.sub.2                                                                        --     267                                      Comp'd 48 H   H   H   CH.sub.3                                                                           3,4-Cl.sub.2                                                                        341    --                                       Comp'd 66 H   H   H   CH.sub.3                                                                           3-Cl 173    --                                       Comp'd 88 H   CH.sub.3                                                                           CH.sub.3                                                                           H   3-Cl --     212                                      Comp'd 89 H   CH.sub.3                                                                           CH.sub.3                                                                           H   4-Cl --     168                                      Comp'd 91 H   CH.sub.3                                                                           CH.sub.3                                                                           H   3,4-Cl.sub.2                                                                        220    --                                       Comp'd 92 H   CH.sub.3                                                                           CH.sub.3                                                                           H   3-CF.sub.3                                                                          361    638                                      Comp'd 94 H   CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           3-Cl --     181                                      Comp'd 95 H   CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           3-CF.sub.3                                                                          186    --                                       Comp'd 96 H   CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           3,4-Cl.sub.2                                                                        186    --                                       Comp'd 44 H   CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           4-Cl --     149                                      Comp'd 49 CH.sub.3                                                                           CH.sub.3                                                                           H   H   3,4-Cl.sub.2                                                                        193    --                                       Comp'd 85 CH.sub.3                                                                           CH.sub.3                                                                           H   H   3-CF.sub.3                                                                          --     193                                      Comp'd 87 CH.sub.3                                                                           CH.sub.3                                                                           H   CH.sub.3                                                                           3-Cl 179    --                                       __________________________________________________________________________      Note:                                                                          "--" means that no measurement was conducted. ("--" will have the same         meaning in the subsequent Tables.)                                       

                  TABLE 1-C                                                        ______________________________________                                          ##STR26##                    (Ic)                                                                     Immune response                                                                potentiation activities                                Sample                  (Control = 100%)                                       compound                                                                               R.sub.1                                                                               R.sub.4                                                                               X.sub.n 0.2 μg/ml                                                                            1 μg/ml                              ______________________________________                                         Comp'd 141                                                                             H      H      3-Cl    750      842                                     Comp'd 137                                                                             H      H      3,4-I.sub.2                                                                            316      561                                     Comp'd 142                                                                             H      H      4-Cl    --       471                                     Comp'd 140                                                                             H      H      2-Cl    --       198                                     Comp'd 144                                                                             H      H      3,4-Cl.sub.2                                                                           405      663                                     Comp'd 145                                                                             H      H      3,5-Cl.sub.2                                                                           318      382                                     Comp'd 155                                                                             H      H      2-Cl, 4-CF.sub.3                                                                       208      439                                     Comp'd 160                                                                             H      CH.sub.3                                                                              3,4-Cl.sub.2                                                                           --       896                                     Comp'd 135                                                                             H      CH.sub.3                                                                              4-Cl    --       230                                     Comp'd 134                                                                             H      CH.sub.3                                                                              3-Cl    520      --                                      Comp'd 166                                                                             H      CH.sub.3                                                                              3,5-(CF.sub.3).sub.2                                                                   339      420                                     Comp'd 136                                                                             H      CH.sub.3                                                                              3-Cl, 4-CF.sub.3                                                                       527      --                                      Comp'd 167                                                                             H      CH.sub.3                                                                              H       --       267                                     Comp'd 138                                                                             CH.sub.3                                                                              H      3,4-Cl.sub.2                                                                           261      839                                     Comp'd 157                                                                             CH.sub.3                                                                              H      3,4-I.sub.2                                                                            239      266                                     ______________________________________                                    

                  TABLE I-D                                                        ______________________________________                                          ##STR27##                                                                                              Immune respon-                                                                 sive potentia-                                                                 tion activities                                                                (Control =                                            Com-                     100%)                                                 pound                              1 μg/                                                                             5 μg/                              No.R.sub.1 R.sub.2                                                                      R.sub.3 R.sub.4 R.sub.5                                                                    A       X.sub.n                                                                              ml    ml                                    ______________________________________                                         171HH    CH.sub.3 CH.sub.3 CH.sub.3                                                                 CH.sub.2                                                                               H     158   --                                    176HH    HHH         CH.sub.2                                                                               4-F   200   --                                    116HH    HHCH.sub.3  (CH.sub.2).sub.2                                                                       H     139   439                                   119HH    CH.sub.3 CH.sub.3 CH.sub.3                                                                 (CH.sub.2).sub.2                                                                       H     611   883                                   117HH    H HCH.sub.3 (CH.sub.2).sub.2                                                                       4-Cl  675   536                                   120HH    CH.sub.3 CH.sub.3 CH.sub.3                                                                 (CH.sub.2).sub.2                                                                       4-Cl  872   883                                   179HH    CH.sub.3 CH.sub.3 H                                                                        (CH.sub.2).sub.2                                                                       2,4-Cl.sub.2                                                                         140   --                                    180HH    HHH         (CH.sub.2).sub.2                                                                       3,4-Cl.sub.2                                                                         205   220                                   181HH    CH.sub.3 CH.sub.3 H                                                                        (CH.sub.2).sub.2                                                                       3,4-Cl.sub.2                                                                         172   173                                   182HH    HHCH.sub.3  (CH.sub.2).sub.2                                                                       3,4-Cl.sub.2                                                                         172   173                                   175HH    CH.sub.3 CH.sub.3 CH.sub.3                                                                 (CH.sub.2).sub.2                                                                       3,4-Cl.sub.2                                                                         505   632                                   183HH    HHH         (CH.sub.2).sub.3                                                                       H     141   200                                   ______________________________________                                    

                  TABLE I-E                                                        ______________________________________                                          ##STR28##                                                                                              Immune re-                                                                     sponsive po-                                                                   tentiation                                                                     activities                                                                     (Control =                                                                     100%)                                                 Com-                                         1    5                            pound                                        μg/                                                                              μg/                       No.   R.sub.1                                                                              R.sub.2                                                                              R.sub.3                                                                             R.sub.4                                                                             R.sub.5                                                                             A     X.sub.n                                                                              ml   ml                           ______________________________________                                         186   H     H     CH.sub.3                                                                            CH.sub.3                                                                            H    CH.sub.2                                                                             4-NO.sub.2                                                                           --   244                          172   H     H     CH.sub.3                                                                            CH.sub.3                                                                            H    (CH.sub.2).sub.2                                                                     H     162  216                          173   H     H     CH.sub.3                                                                            CH.sub.3                                                                            H    (CH.sub.2).sub.2                                                                     4-Cl  --   495                          188   H     H     CH.sub.3                                                                            CH.sub.3                                                                            H    (CH.sub.2).sub. 3                                                                    H     490  373                          189   H     H     H    H    CH.sub.3                                                                            (CH.sub.2).sub.3                                                                     H     268  218                          174   H     H     CH.sub.3                                                                            CH.sub.3                                                                            CH.sub.3                                                                            (CH.sub.2).sub.3                                                                     H     --   196                          ______________________________________                                    

For the sake of comparison, effects on in-vitro plaque forming cell response were also measured in the same manner with respect to the following compounds which are described in Japanese Patent Laid-Open No. 106893/1977 and J. Med. Chem., 24, 604-609 (1981). Results are shown in Table 1-F.

                  TABLE 1-F                                                        ______________________________________                                          ##STR29##                   (VII)                                                                      Immune re-                                                                     sponse po-                                                                     tentiation                                                                     activies                                                                       (Control =                                                                     100%)                                                                                        0.2  1                                  Sample                                 μg/                                                                              μg/                             compound  R.sub.1                                                                              R.sub.3 R.sub.4                                                                             X.sub.n   ml   ml                                 ______________________________________                                         Comparative                                                                              H     H       H    2-F        78  --                                 Compound 1                                                                     Comparative                                                                              H     H       H    2,6-Cl.sub.2                                                                              82  126                                Compound 2                                                                     Comparative                                                                              H     H       H    2,4,6-(CH.sub.3).sub.3                                                                   --   127                                Compound 3                                                                     Comparative                                                                              H     CH.sub.3                                                                               CH.sub.3                                                                            2,4,6-(CH.sub.3).sub.3                                                                   121  132                                Compound 4                                                                     Comparative                                                                              H     CH.sub.3                                                                               H    2,4,6-(CH.sub.3).sub.3                                                                   100  119                                Compound 5                                                                     ______________________________________                                    

As apparent from Table 1-A-Table 1-F, the compounds of this invention showed activities higher than levamisole at a low concentration of 0.2, 1 or 5 μg/ml in the above test in which levamisole required a concentration as high as about 20 μg/ml to exhibit potentiation activities. On the other hand, the comparative compounds exhibited substantially no activities.

TEST 2

Effect on lymphocyte blstogenic response in vitro:

In an RPMI-1640 culture medium (0.2 ml) containing 5% of fetal calf serum (FCS), BALB/C mouse spleen cells (1×10⁵) or thymus cells (2×10⁵) were cultured together with mitogen (Con A: 2.5 μg/ml; or LPS: 10 μg/ml) and a sample compound (1 μg/ml) for 48 hours in a CO₂ incubator (37° C.). Then, 0.5 μCi of ³ H-thymidine was added, followed by further cultivation for 18 hours. The radioactivity of ³ H-thymidine taken in the cells was thereafter measured. Results are summarized in Table 2.

                  TABLE 2                                                          ______________________________________                                                  Incorporation ratio of .sup.3 H--thymidine                                     (Control = 100%)                                                               Spleen cells                                                          Sample compound                                                                           Con A     LPS        Thymus cells                                   (1 μg/ml)                                                                              stimulation                                                                              stimulation                                                                               Con A stimulation                              ______________________________________                                         Compound 141                                                                              131       169        --                                             Compound 142                                                                              166       234        215                                            Compound 144                                                                              148       197        157                                            Compound 135                                                                              182       263        --                                             Compound 145                                                                              133       174        --                                             Compound 134                                                                              136       233        164                                            Compound 48                                                                               136       --         148                                            Compound 91                                                                               151       --         --                                             Compound 163                                                                              140       174        122                                            ______________________________________                                    

The compounds of this invention apparently stimulated the incorporation of ³ H-thymidine.

TEST 3

Effect on lymphocyte blastogenic response in vivo:

A group of six BALB/C mice were used. A sample compound was orally administered at a daily dose of 0.25 mg/Kg, once a day, for 5 days. On the sixth day, spleens were taken out. Spleen cells (2×10⁵) were cultured together with mitogen (Con A: 2.5 μg/ml; or LPS: 10 μg/ml) to investigate the lymphocyte blastogenic response. Culturing conditions were the same as those employed in Test 2 and the measurement of the lymphocyte blastogenic response was effected in accordance with the method used in Test 2. Although levamisole required its administration at a dose of 2.5 mg/Kg/day to show its effects in the present test, the compounds of this invention showed promoting activities equal to or higher than levamisole at a dose one tenth of levamisole, i.e., at a dose of 0.25 mg/Kg/day (Table 3).

                  TABLE 3                                                          ______________________________________                                                     Incorporation ratio of .sup.3 H--thymidine                                     (Control: 100%)                                                    Sample compound                                                                              Con A stimulation                                                                           LPS stimulation                                     ______________________________________                                          Compound 136 240 ± 18  210 ± 9                                           Compound 167 155 ± 10  111 ± 9                                           Compound 134 310 ± 22  125 ± 9                                          Compound 51   142 ± 26   118 ± 12                                        Compound 49   195 ± 8   156 ± 4                                          Compound 91   256 ± 17   176 ± 16                                        Compound 44   155 ± 19  115 ± 6                                          ______________________________________                                    

TEST 4

Effect on delayed-type allergic response:

A group of eight ddY mice were sensitized by injecting 2×10⁸ sheep erythrocytes subcutaneously in the back of each of the mice. On the fourth day after their sensitization, 5×10⁷ sheep erythrocytes were injected under the heel skin of one of the hind legs of each of the mice whereas a physiological saline was injected in the heel skin of the other hind leg. 24 hours later, the thickness of each paw was measured by a micrometer to determine the degree of swelling. Each sample compound was orally administered for 5 days, once a day, after passage of 2 hours from the sensitization. Results are shown in Table 4-A and 4-B. The compounds of this invention inhibited the delayed-type allergic response significantly by its oral administration at a dose of 0.1 mg/Kg/day.

                  TABLE 4-A                                                        ______________________________________                                                                 Degree of swelling (%)                                 Sample     Dose         (average value ±                                    Compound   (mg/Kg/day, po)                                                                             standard deviation)                                    ______________________________________                                         Control    --           29.0 ± 9.0                                          Compound 134                                                                              0.1          15.6 ± 4.0*                                         "          0.2          14.7 ± 4.82*                                        ______________________________________                                          *Significant at a level of P < 0.05 against Control.                     

                  TABLE 4-B                                                        ______________________________________                                                                 Degree of swelling (%)                                 Sample    Dose          (average value ±                                    Compound  (mg/Kg/day, po)                                                                              standard deviation)                                    ______________________________________                                         Control   --            24.2 ± 6.9                                          Compound 44                                                                              0.1           17.1 ± 4.6*                                         ______________________________________                                          *Significant at a level of P < 0.05 against Control.                     

TEST 5

Effect on adjuvant arthritis:

(1) A group of eight Lewis male rats were employed. A suspension of 0.6 mg/0.1 ml of dead cells of Microbacterium tuberculosis in liquid paraffin was injected as an adjuvant in the heel skin of one of the hind legs of each of the rats, thereby inducing adjuvant arthritis. Besides, each sample compound was orally administered once a day for 20 days. On the 21^(st) day, the paw volumes of both hind legs of each of the rats were measured to determine the degree of swelling. Results are shown in Table 5-A.

(2) A suspension of 0.6 mg/0.1 ml of dead cells of Micobacterium tuberculosis in liquid paraffin was injected as an adjuvant in the heel skin of one of the hind legs of each of eight Sprague-Dawley male rats in a group, thereby inducing adjuvant arthritis. From the 21^(st) day after the injection of the adjuvant, each sample compound of this invention was orally administered everyday once a day. The volume of the paw of each hind leg, which was not injected with the adjuvant, was measured on the 7^(th) and 10^(th) days so that the degrees of swelling were determined. Results are shown in Table 5-B.

The compounds of this invention inhibited the swelling of the adjuvant non-injected legs and adjuvant-injected legs significantly when administered at a dose of 1 or 5 mg/Kg/day.

                  TABLE 5-A                                                        ______________________________________                                                         Degree of swelling (%)                                                         (average value ±                                                            standard deviation)                                                                  Adjuvant   Adjuvant                                      Sample   Dose         non-injected                                                                              injected                                      compound (mg/Kg/day, po)                                                                             leg        leg                                           ______________________________________                                         Control  --           173.1 ± 25.5                                                                           309.9 ± 27.1                               Comp'd 44                                                                               1            142.6 ± 29.0*                                                                          285.9 ± 44.9                               Comp'd 44                                                                               5            135.1 ± 27.3*                                                                           274.1 ± 35.4*                             ______________________________________                                          *Significant at a level of P < 0.05 against Control.                     

                  TABLE 5-B                                                        ______________________________________                                                               Degree of swelling (%)                                                         (average value ±                                      Sample   Dose         standard deviation)                                      compound (mg/Kg/day, po)                                                                             7.sup.th day                                                                               10.sup.th day                                ______________________________________                                         Control  --           100.5 ± 31.1                                                                            89.9 ± 28.5                               Comp'd 134                                                                              5             66.0 ± 32.8*                                                                           59.0 ± 27.1*                              ______________________________________                                          *Significant at a level of P < 0.05 against Control.                     

TEST 6

Side effects and blood levels:

To each of four Wistar male rats in a group, each sample compound was orally administered at a dose of 300 mg/Kg, once a day, for 4 days to observe changes in general behaviors and at the same time, to investigate influence on body weight, liver weight and serum cholesterol level. The serum cholesterol level was measured by a Centriphichem Autoanalyzer, using a cholesterol measurement kit marketed by Baker, Inc. Compound 44 and 134 and for certain tests, Compound 2, 3, 30, 31 and 32, were all employed as compounds of this invention, while a compound represented by the general formula (X), in which R₁ =R₃ =R₄ =H and (X)_(n) =3,4-Cl₂ (Comparative Compound 6), and a compound represented along by the general formula (X), in which R₁ =R₃ =R₄ =H and (X)_(n) =3,4-CF₃ (Comparative Compound 7), were both used as comparative compounds. In certain tests, levamisole was also used as a comparative compound. The blood levels of the individual sample compounds were also compared after their single administration and after their administration for four days. Their blood levels were measured by means of a high-performance liquid chromatography.

(1) Effect on the general behaviors:

Although no changes were observed on the general behaviors in the groups administered respectively with the compounds of this invention and Comparative Compound 6, dacryorrhea, dacryohemorrhea, sedation, ataxia and tremor were observed in the group administered with Comparative Compound 7. In the group administered with levamisole, one half of the animals resulted in death.

(2) Effect on the body weight:

Body weights both before administration of the sample compounds and after their continuous administration for 4 days are shown in Table 6-A-Table 6-C.

                  TABLE 6-A                                                        ______________________________________                                                         Body weight, (g)                                                               (average value ±                                                            standard deviation)                                                                  Before      After                                        Sample   Dose         adminis-    administration                               compound (mg/Kg/day, po)                                                                             tration     for 4 days                                   ______________________________________                                         Control  --           79.0 ± 3.5                                                                               93.0 ± 3.4                                Comp'd 30                                                                              300          79.0 ± 2.0                                                                               91.0 ± 0.8                               Control  --           91.3 ± 1.5                                                                              104.0 ± 3.7                                Comp'd 31                                                                              300          91.3 ± 5.5                                                                              102.8 ± 7.8                               Control  --           113.3 ± 1.5                                                                             128.5 ± 3.0                                Comp'd 32                                                                              300          113.8 ± 1.3                                                                             122.0 ± 6.5                               Comp'd 3 300          114.0 ± 5.7                                                                             126.0 ± 8.8                               Control  --           87.0 ± 5.1                                                                              102.8 ± 5.9                               Comp'd 2 300          87.3 ± 2.8                                                                              102.0 ± 1.6                               Comp.    300          87.3 ± 2.5                                                                               89.5 ± 3.0*                              Comp'd 6                                                                       Control  --           93.3 ± 5.7                                                                              108.3 ± 4.9                               Levamisole                                                                              100          93.5 ± 4.7                                                                               99.5 ± 2.5*                              Control  --           111.0 ± 5.3                                                                             128.5 ± 7.0                               Comp.    300          110.0 ± 2.3                                                                              115.3 ± 8.2*                             Comp'd 7                                                                       ______________________________________                                          *Significant at a level of P < 0.05 against Control.                     

                                      TABLE 6-B                                    __________________________________________________________________________                    Test 1        Test 2                                            Sample                                                                               Dose     Before After  Before After                                      compound                                                                             (mg/Kg/day, po)                                                                         administration                                                                        administration                                                                        administration                                                                        administration                             __________________________________________________________________________     Control                                                                              --       84.5 ± 3.1                                                                         100.5 ± 2.5                                                                        87.0 ± 5.1                                                                         102.8 ± 5.9                             Comp'd 44                                                                            300      84.0 ± 1.4                                                                         100.0 ± 2.9                                                                        87.0 ± 2.2                                                                         102.5 ± 3.4                             Comp. 300      84.3 ± 6.1                                                                          88.8 ± 6.4*                                                                       87.3 ± 2.5                                                                          89.5 ± 3.0*                            Comp'd 6                                                                       __________________________________________________________________________      Each value indicates the average body weight (g) of 4 rats in the same         group ± standard deviation.                                                 *Significant at a level of P < 0.05 against Control.                     

                                      TABLE 6-C                                    __________________________________________________________________________                    Test 1          Test 2                                          Sample                                                                               Dose     Before  After   Before  After                                   compound                                                                             (mg/Kg/day, po)                                                                         administration                                                                         administration                                                                         administration                                                                         administration                          __________________________________________________________________________     Control                                                                              --       79.3 ± 1.0                                                                          97.0 ± 3.5                                                                          81.8 ± 2.6                                                                          96.0 ± 2.8                           Comp'd 134                                                                           300      79.5 ± 1.0                                                                          95.8 ± 4.2                                                                          82.0 ± 5.9                                                                          92.0 ± 5.9                           Comp. 300      79.3 ± 1.5                                                                           89.5 ± 3.0*                                                                        --      --                                      Comp'd 6                                                                       __________________________________________________________________________      Each value indicates the average body weight (g) of 4 rats in the same         group ± standard deviation.                                                 *Significant at a level of P < 0.05 against Control.                     

Although neither Compound 44 nor Compound 134 gave any effects to the body weight, Comparative Compound 6 decreased the body weight significantly against Control. Levamisole decreased the body weight significantly against Control even when administered at 100 mg/Kg/day.

(3) Effect on the liver weight:

Results are shown in Table 7-A and Table 7-B. Although Compound 1 did not give any significant effect on the liver weight compared with Control, Comparative Compound 6 increased the liver weight significantly against Control.

                                      TABLE 7-A                                    __________________________________________________________________________                    Test 1        Test 2                                            Sample                                                                               Dose     Liver weight                                                                            Increase                                                                            Liver weight                                                                           Increase                                  compound                                                                             (mg/Kg/day, po)                                                                         (g/100 g B. W. **)                                                                      (%)  (g/100 g B. W.)                                                                        (%)                                       __________________________________________________________________________     Control                                                                              --       4.22 ± 0.03                                                                          --   4.13 ± 0.20                                                                         --                                        Comp'd 44                                                                            300      4.33 ± 0.07                                                                           2.6 4.74 ± 0.65                                                                         14.8                                      Comp. 300       5.35 ± 0.43*                                                                        26.8  5.71 ± 0.27*                                                                       38.3                                      Comp'd 6                                                                       __________________________________________________________________________      Each liver weight indicates the average value of 4 rats in the same group      ± standard deviation.                                                       *Significant at a level of P < 0.05 against Control.                           **B. W. stands for "body weight".                                        

                                      TABLE 7-B                                    __________________________________________________________________________                    Test 1        Test 2                                            Sample                                                                               Dose     Liver weight                                                                            Increase                                                                            Liver weight                                                                           Increase                                  compound                                                                             (mg/Kg/day, po)                                                                         (g/100 g B. W.**)                                                                       (%)  (g/100 g B. W.)                                                                        (%)                                       __________________________________________________________________________     Control                                                                              --       4.30 ± 0.06                                                                          --   4.10 ± 0.22                                                                         --                                        Comp'd 134                                                                           300      4.43 ± 0.21                                                                           3.0 4.13 ± 0.14                                                                          0.7                                      Comp. 300       5.62 ± 0.17*                                                                        30.7  5.50 ± 0.44*                                                                       34.1                                      Comp'd 6                                                                       __________________________________________________________________________      Each liver weight indicates the average value of 4 rats in the same group      ± standard deviation.                                                       *Significant at a level of P < 0.05 against Control.                           **B. W. stands for "body weight".                                        

(4) Effect on the serum cholesterol level:

Test results are shown in Table 8-A and Table 8-B. Neither Compound 44 nor Compound 134 gave any significant effects to the serum cholesterol level compared with Control, Comparative Compound 6 and 7 and Levamisole increased the cholesterol level significantly against Control.

                                      TABLE 8-A                                    __________________________________________________________________________                    Test 1       Test 2                                             Sample                                                                               Dose     Cholesterol                                                                            Increase                                                                            Cholesterol                                                                            Increase                                   compound                                                                             (mg/Kg/day, po)                                                                         (mg/dl) (%)  (mg/dl) (%)                                        __________________________________________________________________________     Control                                                                              --       83.4 ± 7.8                                                                          --   75.2 ± 6.7                                                                          --                                          Comp'd 44                                                                           300      81.3 ± 8.4                                                                          -2.5 82.6 ± 7.1                                                                           9.8                                       Comp. 300       168.3 ± 16.1*                                                                      101.8                                                                                157.1 ± 21.0*                                                                      108.9                                      Comp'd 6                                                                       Control                                                                              --       63.0 ± 6.6                                                                          --   63.0 ± 3.5                                                                          --                                         Comp. 300       83.2 ± 6.2*                                                                        32.1  83.9 ± 5.3*                                                                         33.2                                      Comp'd 7                                                                       Control                                                                              --       73.4 ± 7.5                                                                          --                                                      Levamisole                                                                           100       89.0 ± 4.9*                                                                        21.3                                                    __________________________________________________________________________      Each cholesterol level indicates the average value of 4 rats in the same       group ± standard deviation.                                                 *Significant at a level of P < 0.05 against Control.                     

                                      TABLE 8-B                                    __________________________________________________________________________                    Test 1      Test 2                                              Sample                                                                               Dose     Cholesterol                                                                           Increase                                                                            Cholesterol                                                                            Increase                                    compound                                                                             (mg/Kg/day, po)                                                                         (mg/dl)                                                                               (%)  (mg/dl) (%)                                         __________________________________________________________________________     Control                                                                              --       70.6 ± 7.1                                                                         --   66.2 ± 2.9                                                                          --                                          Comp'd 134                                                                           300      78.5 ± 5.8                                                                         11.2 72.9 ± 6.9                                                                           10.1                                       Comp. 300      134.5 ± 8.3*                                                                       90.5  138.2 ± 17.0*                                                                      108.8                                       Comp'd 6                                                                       __________________________________________________________________________      Each cholesterol level indicates the average value of 4 rats in the same       group ± standard deviation.                                                 *Significant at a level of P < 0.05 against Control.                     

(5) Change in blood level by repeated administration:

Table 9 shows blood levels on the 1^(st) and 2^(nd) hours after each of a single administration and an administration for 4 days, once a day. Although the blood levels of Compounds 44 and 129 were found to be close to their blood levels after their single administration even after the administration for 4 days, the blood levels of Comparative Compounds 6 and 7 dropped remarkably by their repeated administration.

                                      TABLE 9                                      __________________________________________________________________________                     Blood level (μg/ml)                                         Sample Dose     Single administration                                                                       Administration for 4 days                         compound                                                                              (mg/Kg/day, po)                                                                         1 hour later                                                                         2 hours later                                                                         1 hour later                                                                         2 hours later                               __________________________________________________________________________      Comp'd 44                                                                            300      --    12.98 ± 3.81                                                                       --    10.48 ± 1.34                              Comp'd 134                                                                           300      4.48 ± 2.32                                                                       12.15 ± 2.18                                                                       9.75 ± 4.86                                                                       7.70 ± 0.79                              Comp.  300      8.27 ± 2.40                                                                        4.61 ± 0.74                                                                       0.38 ± 0.33                                                                       0.16 ± 0.24                              Comp'd 6                                                                       Comp.  300      8.48 ± 1.91                                                                       10.80 ± 3.53                                                                       3.03 ± 2.08                                                                       2.73 ± 1.14                              Comp'd 7                                                                       __________________________________________________________________________      Each blood level indicates the average value of 4 rats in the same group       ± standard deviation.                                                 

The compounds of this invention may be administered, as they are or in various dosage forms, orally or parenterally (for example, by their intramuscular, subcutaneous, intravenous, rectal or cutaneous administration). As their dosable preparation forms, they may be formed into solid preparations such as tablets, sugar-coated tablets, film-coated tablets, hard and soft capsules, troches, pills, granules and powders; semi-solid preparations such as suppositories, plasters and ointments; and liquid preparations such as injectable solutions, syrups, inhalants, emulsions and suspensions. Although the compounds of this invention may be formed into the above-described preparations without any additional pharmaceutically-effective ingredients, one or more other pharmaceutically-effective ingredients such as nonsteroid analgesic and artiphlogistic agents may also be incorporated in combination.

[EXAMPLES]

The present invention will hereinafter be described further by the following Referential Examples and Examples.

REFERENTIAL EXAMPLE 1

Dissolved in toluene were 3.5 g (0.02 mole) of 3,4-dichloro-N-methylaniline and a catalytic amount of pyridine, followed by a dropwise addition of 1.9 g (0.022 mole) of diketene at 50° C. After completion of the the dropwise addition, the resultant mixture was heated under reflux for 3 hours. The reaction mixture was cooled, and its organic layer was then washed with water, water, a 10% aqueous solution of hydrochloric acid and a 5% aqueous solution of sodium hydrogencarbonate in order. The thus-washed organic solution was dried and concentrated to obtain 3',4'-dichloro-N-methylacetoacetoanilide.

EXAMPLE 1 ##STR30##

(i) Suspended in carbon tetrachloride were 2.6 g (0.01 mole) of the 3',4'-dichloro-N-methylacetoacetoanilide obtained in Referential Example 1 and 1.4 g (0.01 mole) of N-chlorosuccinimide, followed by an addition of a small amount of benzoyl peroxide. The resultant mixture was heated under reflux for 1 hour. The reaction mixture was then washed with water, dried and concentrated. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.0 g (0.01 mole) of imidazolidine-2-thione. The mixture was then heated under reflux for 3 hours. Precipitated crystals were collected by filtration, recrystallized from ethanol and then dried under reduced pressure, thereby obtaining 3.4 g of 3',4'-dichloro-N,3-dimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 1) [yield: 89.5%]. Melting point: 275°-276° C.

(ii) Dissolved in water was 1.9 g (0.005 mole) of the thus-obtained hydrochloride, followed by a dropwise addition with stirring of a 10% aqueous solution of caustic soda at room temperature. Resultant crystals were collected by filtration and washed with a great deal of water to purify same. The thus-washed crystals were dried under reduced pressure to obtain 1.4 g of 3',4'-dichloro-N,3-dimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide (yield: 82.4%). Melting point: 118°-122° C.

EXAMPLE 2 ##STR31##

(i) Suspended in carbon tetrachloride were 1.4 g (0.01 mole) of 3',5'-dichloro-N-methylacetoacetoanilide, obtained in the same manner as in Referential Example 1, and 1.4 g (0.01 mole) of N-chlorosuccinimide, followed by an addition of a small amount of benzoyl peroxide. The resultant mixture was heated under reflux for 1 hour. The reaction mixture was washed with water, dried and then concentrated. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.3 g (0.01 mole) of 4,4-dimethylimidazolidine-2-thione. The resultant mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, recrystallized from isopropanol and then dried under reduced pressure, thereby obtaining 3.0 g of 3',5'-dichloro-N,3,6,6-tetramethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 2) [Yield: 75.0%]. Melting point: 222°-230° C.

(ii) Dissolved in water was 2.0 g (0.005 mole) of the above-obtained hydrochloride, followed by a dropwise addition with stirring of a 20% aqueous solution of potassium carbonate at room temperature. Resultant crystals were collected by filtration and then washed with a great deal of water for its purification. The thus-obtained crystals were dried under reduced pressure to obtain 1.5 g of 3',5'-dichloro-N,3,6,6-tetramethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide (yield: 78.9%). Melting point: 169° C.

EXAMPLE 3 ##STR32##

Dissolved in diethyl ether was 2.6 g (0.01 mole) of N-methyl-4'-trifluoromethylacetoacetoanilide obtained in the same manner as in Referential Example 1, followed by a dropwise addition of 1.5 g (0.011 mole) of sulfuryl chloride at -5° C. The resultant mixture was stirred at -10°--5° C. for 30 minutes. The reaction mixture was then poured into ice water, neutralized with sodium hydrogencarbonate and extracted with toluene. The organic layer was dried and concentrated. The residue was dissolved in methyl ethyl ketone, to which 1.3 g (0.01 mole) of 4,4-dimethylimidazolidine-2-thione was added. The mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, washed with acetone and then dried under reduced pressure, thereby obtaining 3.7 g of N,3,6,6-tetramethyl-4'-trifluoromethyl-5,6-dihydroimidazo-[2,1-b]-thiazole-2-carboxyanilide hydrochloride (Compound 3) [yield: 92.5%]. Melting point: 195°-198° C.

EXAMPLE 4 ##STR33##

Suspended in carbon tetrachloride were 2.7 g (0.01 mole) of 3',4'-dichloro-N-ethylacetoacetoanilide, obtained in the same manner as in Referential Example 1, and 1.4 g (0.01 mole) of N-chlorosuccinimide, followed by an addition of a small amount of benzoyl peroxide. The resultant mixture was heated under reflux for 1 hour. The reaction mixture was washed with water, dried and then concentrated. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.3 g (0.01 mole) of 4,4-dimethylimidazolidine-2-thione. The resultant mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, washed with acetone and then dried under reduced pressure, thereby obtaining 3.3 g of 3',4'-dichloro-N-ethyl-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 4) [yield: 78.6%]. Melting point: 210°-214° C.

EXAMPLE 5 ##STR34##

Following the procedure of Example 2, 2.6 g (0.01 mole) of 3',4'-dichloro-N-methylacetoacetoanilide obtained in Referential Example 1 was chlorinated. The resultant oily substance was dissolved in methyl ethyl ketone, followed by an addition of 1.2 g (0.01 mole) of 4-methylimidazolidine-2-thione. The resulting mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, followed by its washing with acetone to obtain 3.6 g of 3',4'-dichloro-N,3,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 5) [yield: 92.3%]. Melting point: 230°-231° C.

EXAMPLE 6 ##STR35##

Suspended in carbon tetrachloride were 3.2 g (0.01 mole) of N-methyl-3',5'-bis(trifluoromethyl)acetoacetoanilide, obtained in the same manner as in Referential Example 1, and 1.4 g (0.01 mole) of N-chlorosuccinimide, followed by an addition of a small amount of benzoyl peroxide. The resultant mixture was heated under reflux for 1 hour. The reaction mixture was washed with water, dried and then concentrated. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.3 g (0.01 mole) of 4,4-dimethylimidazolidine-2-thione. The resultant mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, washed with acetone and then dried under reduced pressure, thereby obtaining 3.5 g of N,3,5,6-tetramethyl-3',5'-bis(trifluoromethyl)-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 6) [yield: 74.5%]. Melting point: 214°-218° C.

EXAMPLES 7-43

The following compounds were prepared in the same manner as in Referential Example 1 and Examples 1-6.

    __________________________________________________________________________     No.                                                                               R.sub.1                                                                           R.sub.2                                                                          R.sub.3                                                                           R.sub.4                                                                           R.sub.5                                                                             X.sub.n  Appearance      Melting point                      __________________________________________________________________________                                                 (°C.)                        7 H  H H  H  CH.sub.3                                                                            3,4-(OCH.sub.3).sub.2                                                                   Light brownish crystals                                                                        249-253                             8 H  H H  H  CH.sub.3                                                                            4-OC.sub.2 H.sub.5                                                                      White powder    205-209                             9 H  H H  H  H    3,5-(OCH.sub.3).sub.2                                                                   Light Brownish powder                                                                          222-224                            10 H  H H  H  CH.sub.3                                                                            H        Light brownish crystals                                                                        240-242                            11 H  H H  H  CH.sub.3                                                                            4-Cl     Slightly yellowish platy crystals                                                              257-260                            12 H  H H  H  CH.sub.3                                                                            3-OC.sub.3 H.sub.7 --i                                                                  White powder    209-210                            13 H  H H  H  CH.sub.3                                                                            3-CF.sub.3                                                                              White powder    228-235                            14 H  H H  H  CH.sub.3                                                                            2-CH.sub.3, 4-Cl                                                                        Yellowish granular crystals                                                                    267-270                            15 H  H H  H  CH.sub.3                                                                            2-Cl, 4-CF.sub.3                                                                        Brown powder    184-192                            16 H  H H  H  CH.sub.3                                                                            3-Cl     Light yellow powder                                                                            210-215                            17 H  H H  H  CH.sub.3                                                                            3,5-(CF.sub.3).sub.2                                                                    Light yellow powder                                                                            274-276                            18 H  H H  H  CH.sub.3                                                                            4-CF.sub.3                                                                              Yellow powder   235-239                            19 H  H H  H  C.sub.2 H.sub.5                                                                     3,4-Cl.sub.2                                                                            Light brownish crystals                                                                        255-258                            20 H  H H  H  C.sub.2 H.sub.5                                                                     3-CF.sub.3                                                                              Light brownish crystals                                                                        232-234                            21 H  H H  H  C.sub.2 H.sub.5                                                                     2-Cl, 4-CF.sub.3                                                                        Brown crystals  220-229                            22 H  H H  H  C.sub.3 H.sub.7                                                                     3,4-Cl.sub.2                                                                            Milky white crystals                                                                           250-254                            23 H  H H  H  C.sub.3 H.sub.7 --i                                                                 3-OC.sub.3 H.sub.7 --i                                                                  White powder    187-189                            24 H  H H  H  C.sub.3 H.sub.7 --i                                                                 3,4-Cl.sub.2                                                                            Milky white crystals                                                                           250-254                            25 H  H H  H  C.sub.3 H.sub.7 --i                                                                 4-Cl     White crystals  228-231                            26 H  H H  H  C.sub.3 H.sub.7 --i                                                                 3-CF.sub.3                                                                              Light brownish crystals                                                                        197-198                            27 H  H H  H  C.sub.3 H.sub.7 --i                                                                 3,5-Cl.sub.2                                                                            White powder    250-254                            28 CH.sub.3                                                                          H CH.sub.3                                                                          H  CH.sub.3                                                                            4-F      Milky white powder                                                                             195-198                            29 H  H CH.sub.3                                                                          H  CH.sub.3                                                                            3-Cl     Dark yellow powder                                                                             unmeasurable                       30 H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                            3-CF.sub.3                                                                              Milky white powder                                                                             202-210                            31 H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                            3,4-Cl.sub.2                                                                            Light brownish crystals                                                                        202-206                            32 H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                            3,5-(CF.sub.3).sub.2                                                                    Yellowish brown powder                                                                         168-170                            33 H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                            2-Cl, 4-CF.sub.3                                                                        Light brownish crystals                                                                        222-224                            34 H  H CH.sub.3                                                                          CH.sub.3                                                                          C.sub.2 H.sub.5                                                                     2-Cl, 4-CF.sub.3                                                                        Light brownish platy crystals                                                                  230-235                            35 H  H CH.sub.3                                                                          CH.sub.3                                                                          C.sub.2 H.sub.5                                                                     3-CF.sub.3                                                                              Yellow crystals 51-52                              36 H  H CH.sub.3                                                                          CH.sub.3                                                                          C.sub.3 H.sub.7                                                                     3,4-Cl.sub.2                                                                            White crystals  214-218                            37 H  H CH.sub.3                                                                          CH.sub.3                                                                          C.sub.3 H.sub.7 --i                                                                 3,4-Cl.sub.2                                                                            Milky white crystals                                                                           220-225                            38 H  H CH.sub.3                                                                          CH.sub.3                                                                          C.sub.3 H.sub.7 --i                                                                 4-Cl     White crystals  245-250                            39 H  H CH.sub.3                                                                          CH.sub.3                                                                          C.sub.3 H.sub.7 --i                                                                 3-CF.sub.3                                                                              Light yellowish crystals                                                                       unmeasurable                       40 H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                            4-NO.sub.2                                                                              Light yellowish crystals                                                                       177-182                            41 H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                            4-F      Milky white powder                                                                             184-186                            42 H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                            3,5-Cl.sub.2,4-C.sub.5 H.sub.11 O                                                       Brown powder    209-212                            43 H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                            2,3,4,5,6-F.sub.5                                                                       Light yellowish powder                                                                         216-222                            __________________________________________________________________________

REFERENTIAL EXAMPLE 2

Dissolved in toluene was 3.1 g (0.02 mole) of 4-chloro-N-methyl-benzylamine, followed by an addition of a catalytic amount of pyridine and a further dropwise addition of 1.8 g (0.022 mole) of diketene at room temperature. After stirring the reaction mixture at room temperature for 3 hours, it was poured in water and then extracted with toluene. Subsequent to purification, N-methyl-N-(4-chlorobenzyl)acetamide was obtained in an oily form.

EXAMPLE 44 ##STR36##

(i) Suspended in carbon tetrachloride were 4.0 g (0.017 mole) of N-methyl-N-(4-chlorobenzyl)acetoacetamide obtained in Referential Example 2, 2.3 g (0.017 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The suspension was heated under reflux for 1 hour. After cooling the reaction mixture, it was poured into water and then extracted with carbon tetrachloride. The carbon tetrachloride solution was purified, dried and concentrated, thereby obtaining an oily crude product. The crude product was purified on a silica gel column (c-300, n-hexane-ethyl acetate) to obtain 3.5 g of oily N-methyl-N-(4-chlorobenzyl)-2-chloroacetamide (n_(D) ²⁰ : 1.5336). The reaction product was then dissolved together with 1.7 g (0.013 mole) of 4,4-dimethylimidazolidine-2-thione in methyl ethyl ketone. The resultant mixture was heated under reflux for 3 hours. After cooling, the resultant precipitate was collected by filtration, washed with acetone and then recrystallized from isopropanol/isopropyl ether, thereby obtaining 4.8 g of N-(4-chlorobenzyl)-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide hydrochloride as (Compound 44) [melting point: 187°-190° C.; white crystals].

(ii) Dissolved in water was 3.9 g (0.01 mole) of the above-obtained hydrochloride. While stirring the thus-prepared aqueous solution at room temperature, a 10% aqueous solution of caustic soda was added dropwise. Resulting crystals were collected by filtration and then washed with a great deal of water to purify same. The crystals were thereafter dried under reduced pressure to obtain 3.3 g of N-(4-chlorobenzyl)-N,3,6,6-tetramethyl-5,6-dihydroimidazo[2,1-b)thiazole-2-carboxamide (melting point: 139° C.; light yellowish powdery crystals).

EXAMPLE 45 ##STR37##

Suspended in carbon tetrachloride were 2.3 g (0.01 mole) of N-(4-chlorobenzyl)acetoacetamide obtained in the same manner as in Referential Example 2, 1.3 g (0.01 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The suspension was heated under reflux for 1 hour. The reaction mixture was then poured into water and extracted with carbon tetrachloride. The carbon tetrachloride solution was washed with water, dried and then concentrated. The resultant oily substance was provided for the following reaction without purifying same beforehand. Namely, the thus-obtained compound and 1.0 g (0.01 mole) of imidazolidine-2-thione were suspended in methyl ethyl ketone and the resultant suspension was heated under reflux for 3 hours. After cooling the reaction mixture, the resultant precipitate was collected by filtration, washed with acetone and then recrystallized from isopropyl alcohol/isopropyl ether, thereby obtaining 2.8 g of N-(4-chlorobenzyl)-3-methyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide hydrochloride (Compound 45). Melting point: 241°-242° C. White crystals.

EXAMPLE 46 ##STR38##

Suspended in carbon tetrachloride were 2.6 g (0.01 mole) of N-(3-trifluoromethylbenzyl)acetoacetamide obtained in the same manner as in Referential Example 2, 1.3 g (0.01 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The suspension was heated under reflux for 1 hour. After cooling the reaction mixture, it was poured into water and extracted with carbon tetrachloride. The carbon tetrachloride solution was washed with water, dried and then concentrated. The resultant oily substance was provided for the following reaction without purifying same beforehand. Namely, the thus-obtained compound and 1.0 g (0.01 mole) of imidazolidine-2-thione were suspended in methyl ethyl ketone and the resultant suspension was heated under reflux for 3 hours. After cooling the reaction mixture, the resultant precipitate was collected by filtration, washed with acetone and then recrystallized from ethanol, thereby obtaining 2.5 g of 3-methyl-N-(3-trifluoromethylbenzyl)-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide hydrochloride (Compound 46) [melting point: 210°-216° C.; colorless prism-like crystals].

EXAMPLE 47 ##STR39##

Suspended in carbon tetrachloride were 2.5 g (0.01 mole) of N-ethyl-N-(4-chlorobenzyl)acetoacetamide obtained in the same manner as in Referential Example 2, 1.3 g (0.01 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The suspension was heated under reflux for 1 hour. After cooling the reaction mixture, it was poured into water and extracted with carbon tetrachloride. The carbon tetrachloride solution was washed with water, dried and then concentrated. The resultant oily substance was provided for the following reaction without purifying same beforehand. Namely, the thus-obtained compound and 1.3 g (0.01 mole) of 4,4-dimethylimidazolidine-2-thione were dissolved in methyl ethyl ketone and the resultant solution was heated under reflux for 3 hours. After cooling the reaction mixture, the resultant precipitate was collected by filtration, washed with acetone and then recrystallized from isopropanol/isopropyl ether, thereby obtaining 2.7 g of N-(4-chlorobenzyl)-N-ethyl-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide hydrochloride (Compound 47) [melting point: 186°-188° C.; white crystals].

EXAMPLE 48 ##STR40##

Suspended in carbon tetrachloride were 2.6 g (0.01 mole) of N-methyl-N-(3,4-dichlorobenzyl)acetoacetamide obtained in the same manner as in Referential Example 2, 1.3 g (0.01 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The suspension was heated under reflux for 1 hour. After cooling the reaction mixture, it was poured into water and extracted with carbon tetrachloride. The carbon tetrachloride solution was washed with water, dried and then concentrated. The resultant oily substance was provided for the following reaction without purifying same beforehand. Namely, the thus-obtained compound and 1.0 g (0.01 mole) of imidazolidine-2-thione were suspended in methyl ethyl ketone and the resultant suspension was heated under reflux for 3 hours. After cooling the reaction mixture, the resultant precipitate was collected by filtration, washed with acetone and then recrystallized from ethanol, thereby obtaining 3.1 g of N-(3,4-dichlorobenzyl)-N,3-dimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide hydrochloride (Compound 48) [melting point: 196°-198° C.; light yellowish needle-like crystals].

EXAMPLE 49 ##STR41##

Suspended in carbon tetrachloride were 5.2 g (0.02 mole) of N-(3,4-dichlorobenzyl)acetoacetamide obtained in the same manner as in Referential Example 2, 2.7 g (0.02 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The suspension was heated under reflux for 1 hour. After cooling the reaction mixture, it was poured into water and extracted with carbon tetrachloride. The carbon tetrachloride solution was washed with water, dried and then concentrated. The resultant oily substance was provided for the following reaction without purifying same beforehand. Namely, the thus-obtained compound and 2.6 g (0.02 mole) of 4,5-dimethylimidazolidine-2-thione were dissolved in methyl ethyl ketone and the resultant solution was heated under reflux for 3 hours. After cooling the reaction mixture, the resultant precipitate was collected by filtration and then washed and purified with a great deal of acetone, thereby obtaining N-(3,4-dichlorobenzyl)-3,5,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide hydrochloride (Compound 49) [melting point: 148°-152° C.; white crystals].

EXAMPLE 50 ##STR42##

Suspended in carbon tetrachloride were 4.8 g (0.02 mole) of N-(3-chlorobenzyl)-N-methylacetamide obtained in the same manner as in Referential Example 2, 2.7 g (0.02 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The suspension was heated under reflux for 1 hour. It was then poured into water and extracted with carbon tetrachloride. The carbon tetrachloride solution was washed with water, dried and then concentrated. The resultant oily substance was provided for the following reaction without purifying same beforehand. Namely, the thus-obtained compound and 2.4 g (0.02 mole) of 4-methylimidazolidine-2-thione were dissolved in methyl ethyl ketone and the resultant solution was heated under reflux for 3 hours. After cooling the reaction mixture, the resultant precipitate was collected by filtration and then washed and purified with acetone and isopropyl ether, thereby obtaining N-(3-chlorobenzyl)-N,3,6-trimethyl-5,6-dihydroimidazo[2,1-b]-hiazole-2-carboxamide hydrochloride (Compound 50) [melting point: 41°-47° C.; brownish glassy matter].

EXAMPLE 51 ##STR43##

(i) Suspended in carbon tetrachloride were 5.2 g (0.02 mole) of N-(2,4-dichlorobenzyl)-N-methylacetamide obtained in the same manner as in Referential Example 2, 2.7 g (0.02 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The suspension was heated under reflux for 1 hour. After cooling the reaction mixture, it was poured into water and extracted with carbon tetrachloride. The carbon tetrachloride solution was washed with water, dried and then concentrated. The resultant oily substance was provided for the following reaction without purifying same beforehand. Namely, the thus-obtained compound and 1.0 g (0.01 mole) of imidazolidine-2-thione were suspended in methyl ethyl ketone and the resultant suspension was heated under reflux for 3 hours. After cooling the reaction mixture, the resultant precipitate was collected by filtration and then washed and purified with acetone, thereby obtaining 5.3 g of N-(2,4-dichlorobenzyl)-N,3-dimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide hydrochloride (Compound 51) [melting point: 251°-255° C.; colorless power].

(ii) Dissolved in water was 3.6 g (0.01 mole) of the thus-obtained 2-[N-methyl-N-(2,4-dichlorobenzyl)carbamoyl]-3-methyl-5,6-dihydroimidazo[2,1-b]thiazole hydrochloride. While stirring the solution at room temperature, aqueous ammonia was added dropwise. The resultant precipitate was collected by filtration and then washed and purified with a great deal of water, thereby obtaining 3.0 g of N-(2,4-dichlorobenzyl)-N,3-dimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide (melting point: 55°-60° C.; light yellowish crystals).

EXAMPLES 52-133

The following compounds were prepared in the same manner as in Referential Example 2 and Examples 44- 51.

    __________________________________________________________________________      ##STR44##                                                                     Compound                                                                       No.   R.sub.1                                                                           R.sub.2                                                                          R.sub.3                                                                           R.sub.4                                                                           R.sub.6                                                                              A      X.sub.n                                                                               Appearance      Melting point                                                                  (°C.)              __________________________________________________________________________     52    H  H H  H  H     CH.sub.2                                                                              H      White prism-like crystals                                                                      260-270                   53    H  H H  H  H     CH.sub.2                                                                              2-Cl   Black prism-like crystals                                                                      242-250                   54    H  H H  H  H     CH.sub.2                                                                              3-Cl   White powder    233-235                   55    H  H H  H  H     CH.sub.2                                                                              2,4-Cl.sub.2                                                                          Colorless crystals                                                                             275                       56    H  H H  H  H     CH.sub.2                                                                              3,4-Cl.sub.2                                                                          Colorless fine  273                                                            needle-like crystals                      57    H  H H  H  H     CH.sub.2                                                                              4-CH.sub.3                                                                            White powder    233-235                   58    H  H H  H  H     CH.sub.2                                                                              4-OCH.sub.3                                                                           Light yellowish crystals                                                                       192-194                   59    H  H H  H  H     CH.sub.2                                                                              4-NO.sub.2                                                                            White powder    243-248                   60    H  H H  H  H     CH.sub.2                                                                              3,5-Cl.sub.2                                                                          Milky white crystals                                                                           250-253                   61    H  H H  H  CH.sub.3                                                                             CH.sub.2                                                                              H      White prism-like crystals                                                                      187-189                   62    H  H H  H  CH.sub.3                                                                             CH.sub.2                                                                              2-Cl   Light yellowish powder                                                                         189-192                   63    H  H H  H  CH.sub.3                                                                             CH.sub.2                                                                              4-Cl   Light yellowish 126-130                                                        prism-like crystals                       64    H  H H  H  CH.sub.3                                                                             CH.sub.2                                                                              4-CH.sub.3                                                                            Light brownish crystals                                                                        195-197                   65*   H  H H  H  CH.sub.3                                                                             CH.sub.2                                                                              4-OCH.sub.3                                                                           White crystals  118-119                   66    H  H H  H  CH.sub.3                                                                             CH.sub.2                                                                              3-Cl   Yellowish brown glassy                                                                         52-58r                    67    H  H H  H  CH.sub.3                                                                             CH.sub.2                                                                              3-CF.sub.3                                                                            Yellowish brown crystals                                                                       31-34                     68    H  H H  H  CH.sub.3                                                                             CH.sub.2                                                                              3,5-Cl.sub.2                                                                          Milky white crystals                                                                           194-195                   69    H  H H  H  CH.sub. 3                                                                            CH.sub.2                                                                              4-F    Light brownish powder                                                                          173-175                   70    H  H H  H  CH.sub.3                                                                             CH.sub.2                                                                              4-CF.sub.3                                                                            Milky white powder                                                                             212-215                   71    H  H H  H  CH.sub.3                                                                             CH.sub.2                                                                              4-OC.sub.2 H.sub.5                                                                    Milky white powder                                                                             179-180                   72    H  H H  H  CH.sub.3                                                                             CH.sub.2                                                                              4-C.sub.2 H.sub.5                                                                     Light brownish crystals                                                                        195-200                   73    H  H H  H  CH.sub.3                                                                             CH.sub.2                                                                              4-NO.sub.2                                                                            Pinkish powder  236-238                   74    H  H H  H  C.sub.2 H.sub.5                                                                      CH.sub.2                                                                              4-Cl   White crystals  202-205                   75    H  H H  H  C.sub.2 H.sub.5                                                                      CH.sub.2                                                                              3,4-Cl.sub.2                                                                          Milky white crystals                                                                           247-250                   76    H  H H  H  C.sub.2 H.sub.5                                                                      CH.sub.2                                                                              3-CF.sub.3                                                                            Light brownish crystals                                                                        170-175                   77    H  H H  H  n-C.sub.3 H.sub.7                                                                    CH.sub.2                                                                              3,4-Cl.sub.2                                                                          Milky white crystals                                                                           233-237                   78    H  H H  H  i-C.sub.3 H.sub.7                                                                    CH.sub.2                                                                              4-Cl   White crystals  225-230                   79    H  H H  H  i-C.sub.3 H.sub.7                                                                    CH.sub.2                                                                              3-Cl   Light brownish crystals                                                                        202-205                   80    H  H H  H  i-C.sub.3 H.sub.7                                                                    CH.sub.2                                                                              3-CF.sub.3                                                                            Yellowish crystals                                                                             233-236                   81    H  H H  H  i-C.sub.4 H.sub.9                                                                    CH.sub.2                                                                              4-Cl   White crystals  237-238                   82    H  H CH.sub.3                                                                          H  H     CH.sub.2                                                                              3-Cl   Milky white powder                                                                             148-150                   83    CH.sub.3                                                                          H CH.sub.3                                                                          H  H     CH.sub.2                                                                              2,4-Cl.sub.2                                                                          White powder    170-172                   84    CH.sub.3                                                                          H CH.sub.3                                                                          H  H     CH.sub.2                                                                              4-Cl   White powder    166-167                   85    CH.sub.3                                                                          H CH.sub.3                                                                          H  H     CH.sub.2                                                                              3-CF.sub.3                                                                            Light brownish glassy                                                                          unmeasurable              86    CH.sub.3                                                                          H CH.sub.3                                                                          H  H     CH.sub.2                                                                              3-Cl   White crystals  171-173                   87    CH.sub.3                                                                          H CH.sub.3                                                                          H  CH.sub.3                                                                             CH.sub.2                                                                              3-Cl   Brownish glassy matter                                                                         unmeasurable              88    H  H CH.sub.3                                                                          CH.sub.3                                                                          H     CH.sub.2                                                                              3-Cl   Yellowish brown powder                                                                         80-93                     89    H  H CH.sub.3                                                                          CH.sub.3                                                                          H     CH.sub.2                                                                              4-Cl   Slightly brownish crystals                                                                     70-79                     90    H  H CH.sub.3                                                                          CH.sub.3                                                                          H     CH.sub.2                                                                              2,4-Cl.sub.2                                                                          White crystals  219-222                   91    H  H CH.sub.3                                                                          CH.sub.3                                                                          H     CH.sub.2                                                                              3,4-Cl.sub.2                                                                          Light yellowish crystals                                                                       107-115                   92    H  H CH.sub.3                                                                          CH.sub.3                                                                          H     CH.sub.2                                                                              3-CF.sub.3                                                                            Ocher powder    55-63                     93    H  H CH.sub.3                                                                          CH.sub.3                                                                          H     CH.sub.2                                                                              3,5-Cl.sub.2                                                                          Brown glassy matter                                                                            unmeasurable              94    H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.2                                                                              3-Cl   Brown glassy matter                                                                            unmeasurable              95    H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.2                                                                              3-CF.sub.3                                                                            Brown syrupy matter                                                                            unmeasurable              96    H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.2                                                                              3,4-Cl.sub.2                                                                          Light brownish glassy                                                                          unmeasurable              97    H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.2                                                                              3,5-Cl.sub.2                                                                          Yellowish crystals                                                                             unmeasurable              98    H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.2                                                                              4-F    Ocher solid matter                                                                             155-156                   99    H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.2                                                                              4-CF.sub.3                                                                            Milky white powder                                                                             218-220                   100   H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.2                                                                              4-CN   Pinkish powder  234-237                   101   H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.2                                                                              2,4,6-(CH.sub.3).sub.3                                                                White powder    228-235                   102   H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.2                                                                              2,3,4,5,6-F.sub.5                                                                     White powder    180-181                   103   H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.2                                                                              4-OC.sub.2 H.sub.5                                                                    Milky white powder                                                                             151-152                   104   H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.2                                                                              4-OCH.sub.3                                                                           White crystals  165-168                   105   H  H CH.sub.3                                                                          CH.sub. 3                                                                         CH.sub.3                                                                             CH.sub.2                                                                              4-C.sub.2 H.sub.5                                                                     Milky white powder                                                                             205-212                   106   H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.2                                                                              4-NO.sub.2                                                                            Milky white powder                                                                             217-221                   107   H  H CH.sub.3                                                                          CH.sub.3                                                                          C.sub.2 H.sub.5                                                                      CH.sub.2                                                                              3,4-Cl Milky white crystals                                                                           185-187                   108   H  H CH.sub.3                                                                          CH.sub.3                                                                          C.sub.2 H.sub.5                                                                      CH.sub.2                                                                              3-CF.sub.3                                                                            Light brownish crystals                                                                        107-108                   109   H  H CH.sub.3                                                                          CH.sub.3                                                                          n-C.sub.3 H.sub.7                                                                    CH.sub.2                                                                              3,4-Cl.sub.2                                                                          Milky white crystals                                                                           210-213                   110   H  H CH.sub.3                                                                          CH.sub.3                                                                          i-C.sub.3 H.sub.7                                                                    CH.sub.2                                                                              3,4-Cl.sub.2                                                                          White crystals  235-240                   111   H  H CH.sub.3                                                                          CH.sub.3                                                                          i-C.sub.3 H.sub.7                                                                    CH.sub.2                                                                              4-Cl   White crystals  222-223                   112   H  H H  H  H                                                                                     ##STR45##                                                                            4-Cl   White crystals  208-209                   113   H  H H  H  H                                                                                     ##STR46##                                                                            3-Cl   White crystals  160-162                   114   H  H H  H  H                                                                                     ##STR47##                                                                            3,4-Cl.sub.2                                                                          White crystals  233-236                   115   H  H H  H  H      (CH.sub.2).sub.2                                                                     4-Cl   Milky white crystals                                                                           193-196                   116   H  H H  H  CH.sub.3                                                                             (CH.sub.2).sub.2                                                                      H      Colorless powder                                                                               184-185                   117   H  H H  H  CH.sub.3                                                                             (CH.sub.2).sub.2                                                                      4-Cl   Colorless powder                                                                               195-197                   118   H  H H  H  CH.sub.3                                                                             (CH.sub.2).sub.2                                                                      4-CH.sub.3                                                                            Light yellow powder                                                                            197-198                   119   H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                             (CH.sub.2).sub.2                                                                      H      Light yellow powder                                                                            180-182                   120   H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                             (CH.sub.2).sub.2                                                                      4-Cl   Light yellow powder                                                                            193-195                   121   H  H H  H  H                                                                                     ##STR48##                                                                            3-Cl   White powder    249-256                   122   H  H H  H  H                                                                                     ##STR49##                                                                            2-Cl   White crystals  255-258                   123   H  H H  H  H                                                                                     ##STR50##                                                                            4-Cl   White crystals  240-244                   124   H  H H  H  H                                                                                     ##STR51##                                                                            2,4-Cl.sub.2                                                                          Milky white crystals                                                                           250-253                   125   H  H H  H  CH.sub.3                                                                              ##STR52##                                                                            2-Cl   Milky white crystals                                                                           242-244                   126   H  H CH.sub.3                                                                          CH.sub.3                                                                          H                                                                                     ##STR53##                                                                            2-Cl   White crystals  212-216                   127   H  H CH.sub.3                                                                          CH.sub.3                                                                          H                                                                                     ##STR54##                                                                            4-Cl   Light yellowish flaky                                                                          170-172s                  128   H  H CH.sub.3                                                                          CH.sub.3                                                                          H                                                                                     ##STR55##                                                                            2,4-Cl.sub.2                                                                          White crystals  240-246                   129   H  H CH.sub.3                                                                          CH.sub.3                                                                          H                                                                                     ##STR56##                                                                            3-Cl   Milky white crystals                                                                           119-125                   130   H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                              ##STR57##                                                                            2-Cl   White crystals  255-257                   131   H  H H  H                                                                                  ##STR58##                                                                           CH.sub.2                                                                              4-Cl   White down-like crystals                                                                       215-220                   132   H  H CH.sub.3                                                                          CH.sub. 3                                                                          ##STR59##                                                                           CH.sub.2                                                                              4-Cl   White down-like crystals                                                                       250-253                   __________________________________________________________________________      Asterisk (*) indicates that the compound is a free base.                 

REFERENTIAL EXAMPLE 3

Dissolved in toluene were 2.5 g (0.02 mole) of m-chloroaniline and a catalytic amount of pyridine, followed by dropwise addition of 1.9 g (0.022 mole) of diketene at 50° C. After completion of the dropwise addition, the resultant mixture was heated under reflux for 3 hours. Under ice-cooling, ligroin was added, and precipitated crystals were collected by filtration and were then washed first with ligroin and then with hexane. The crystals were then dried under reduced pressure to obtain 3'-chloroacetoacetanilide.

EXAMPLE 133 ##STR60##

(i) Dissolved in diethyl ether was 2.1 g (0.01 mole) of the 3'-chloroacetanilide obtained in Referential Example 3, followed by a dropwise addition of 1.5 g (0.011 mole) of sulfuryl chloride at -5° C. The resultant mixture was stirred at -10°--5° C. for 30 minutes. The reaction mixture was poured into ice water, neutralized with sodium hydrogencarbonate and then extracted with toluene. The organic layer was dried and concentrated. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.3 g (0.01 mole) of 4,4-dimethylimidazolidine-2-thione. The mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, recrystallized from isopropanol, and then dried at 120° C. under reduced pressure for 3 hours. The crystals were then suspended in methyl ethyl ketone and heated under reflux for 20 hours. The reaction mixture was cooled, and the resultant precipitate was collected by filtration, washed with acetone and then dried under reduced pressure to obtain 2.6 g of 3'-chloro-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 133) [yield: 72.2%]. PMR ppm δ(DMSO-d₆): 1.53 (6H, s, 6.6(CH₃)₂), 2.53 (3H, s, 3,-CH₃), 4.27 (2H, s, 5-CH₂ --), 7.03-8.00 (4H, m, aromatic proton), 10.80 (1H, s, --NH-- ).

(ii) Dissolved in water was 1.8 g (0.005 mole) of the thus-obtained 3'-chloro-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride. While stirring the aqueous solution at room temperature, a 20% aqueous solution of potassium carbonate was added dropwise. The resultant precipitate was collected by filtration and then washed and purified with a great deal of water. The precipitate was then dried under reduced pressure to obtain 1.3 g of 3'-chloro-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide (melting point: 172°-173° C.; milky white powder).

EXAMPLE 134 ##STR61##

(i) Dissolved in diethyl ether was 2.1 g (0.01 mole) of 4'-chloroacetanilide obtained in the same manner as in Referential Example 3, followed by a dropwise addition of 1.5 g (0.011 mole) of sulfuryl chloride at -5° C. The resultant mixture was stirred at -10°--5° C. for 30 minutes. The reaction mixture was poured in ice water, neutralized with sodium hydrogencarbonate and then extracted with toluene. The organic layer was dried and concentrated. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.3 g (0.01 mole) of 4,4-dimethylimidazolidine-2-thione. The mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, washed with acetone and then dried under reduced pressure to obtain 3.4 g 4'-chloro-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 134) [yield: 94.4%]. Melting point: 264°-268° C.

(ii) Dissolved in water was 1.8 g (0.005 mole) of the thus-obtained 4'-chloro-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride. While stirring the aqueous solution at room temperature, a 10% aqueous solution of caustic soda was added dropwise. The resultant precipitate was collected by filtration and then washed and purified with a great deal of water. The precipitate was then dried under reduced pressure to obtain 1.0 g of 4'-chloro-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]-thiazole-2-carboxyanilide (melting point: 235°-236° C.; white powder).

EXAMPLE 135 ##STR62##

(i) Dissolved in carbon tetrachloride were 2.8 g (0.01 mole) of 2'-chloro-4'-trifluoromethylacetoacetanilide obtained in the same manner as in Referential Example 3 and 1.4 g (0.01 mole) of N-chlorosuccinimide, followed by an addition of a small amount of benzoyl peroxide. The resultant suspension was heated under reflux for 1 hour. The reaction mixture was washed with water, dried and then concentrated. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.3 g (0.01 mole) of 4,4-dimethylimidazolidine-2-thione. The mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, recrystallized from isopropyl ether-ethanol and then dried at 120° C. under reduced pressure for 3 hours to obtain 2.5 g of 2'-chloro-4'-trifluoromethyl-3,6,6-trimethyl-5,6-dihydroimidazo-[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 135) [yield: 61.9%]. Melting point: 148°-150° C.

EXAMPLE 136 ##STR63##

Dissolved in carbon tetrachloride were 4.3 g (0.01 mole) of 3',4'-diiodoacetoacetanilide obtained in the same manner as in Referential Example 3 and 1.4 g (0.01 mole) of N-chlorosuccinimide, followed by an addition of a small amount of benzoyl peroxide. The resultant suspension was heated under reflux for 1 hour. The reaction mixture was washed with water, dried and then concentrated. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.2 g (0.01 mole) of 4-methylimidazolidine-2-thione. The mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, washed with acetone and then dried under reduced pressure to obtain 4.8 g of 3',4'-diiodo-3,6-dimethyl-5,6-dihydroimidazo-[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 136) [yield: 85.7%]. Melting point: 278°-280° C.

EXAMPLE 137 ##STR64##

Dissolved in carbon tetrachloride were 2.5 g (0.01 mole) of 3',4'-dichloroacetoacetanilide obtained in the same manner as in Referential Example 3 and 1.4 g (0.01 mole) of N-chlorosuccinimide, followed by an addition of a small amount of benzoyl peroxide. The resultant suspension was heated under reflux for 1 hour. The reaction mixture was washed with water, dried and then concentrated. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.3 g (0.01 mole) of 4,5-dimethylimidazolidine-2-thione. The mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, recrystallized from isopropyl ether-ethanol, and then dried at 120° C. under reduced pressure for 3 hours to obtain 2.5 g of 3',4'-dichloro-3,5,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 137) [yield: 64.1%]. Melting point: 240°-245° C.

EXAMPLES 138-170

The following compounds were obtained in the same manner as in Referential Example 3 and Examples 133-137.

    ______________________________________                                          ##STR65##                                                                                                             Melting                                                                        point                                  No.  R.sub.1                                                                               R.sub.2                                                                               X.sub.n   Appearance (°C.)                           ______________________________________                                         138  H      H      H         Yellowish powder                                                                          207-209                                139  H      H      2-Cl      White powder                                                                              205-212                                140  H      H      3-Cl      White powder                                                                              196-198                                141  H      H      4-Cl      Yellowish powder                                                                          240-244                                142  H      H      2,4-Cl.sub.2                                                                             White powder                                                                              245-253                                143  H      H      3,4-Cl.sub.2                                                                             Yellowish powder                                                                          234-235                                144  H      H      3,5-Cl.sub.2                                                                             Yellowish powder                                                                          255-259                                145  H      H      3-Br      White powder                                                                              201-204                                146  H      H      4-NO.sub.2                                                                               Light yellowish                                                                           255-258                                                             powder                                            147  H      H      3-I       White powder                                                                              203-204                                148  H      H      4-I       White powder                                                                              270                                    149  H      H      2-CH.sub.3                                                                               White powder                                                                              241-246                                150  H      H      4-CH.sub.3                                                                               Milky white                                                                               208-210                                                             powder                                            151  H      H      2-OCH.sub.3                                                                              White powder                                                                              245-253                                152  H      H      4-OCH.sub.3                                                                              White powder                                                                              210-215                                153  H      H      3-OC.sub.3 H.sub.7i                                                                      White powder                                                                              115-122                                154  H      H      2-Cl, 4-CF.sub.3                                                                         White powder                                                                              138-142                                155  H      H      3-Cl, 4-F Gray powder                                                                               150-154                                156  CH.sub.3                                                                              H      3,4-I.sub.2                                                                              Brown powder                                                                              214-215                                157  CH.sub.3                                                                              H      4-Cl      White powder                                                                              259-264                                158  CH.sub.3                                                                              H      2-Cl, 4-CF.sub.3                                                                         White flaky                                                                               178-182                                                             crystals                                          159  H      CH.sub.3                                                                              3,4-Cl.sub.2                                                                             Brown syrupy                                                                              128-136                                                             matter                                            160  H      CH.sub.3                                                                              2,4-Cl.sub.2                                                                             Light orange                                                                              172-175                                                             crystals                                          161  H      CH.sub.3                                                                              3,5-Cl.sub.2                                                                             Yellowish crystals                                                                        155-160                                162  H      CH.sub.3                                                                              3,4-I.sub.2                                                                              Light brownish                                                                            266-268                                                             crystals                                          163  H      CH.sub.3                                                                              4-I       White crystals                                                                            220-225                                164  H      CH.sub.3                                                                              3-Cl, 4-F Gray powder                                                                               251-256                                165  H      CH.sub.3                                                                              3,5-(CF.sub.3).sub.2                                                                     Gray powder                                                                               261-265                                166  H      CH.sub.3                                                                              H         White crystals                                                                            240-245                                167  H      CH.sub.3                                                                              4-Br      White crystals                                                                            255-261                                168  H      CH.sub.3                                                                              2,5-(OCH.sub.3).sub.2                                                                    Milky white                                                                               245-247                                                             powder                                            169  H      CH.sub.3                                                                              2-OCH.sub.3, 5-OH                                                                        Yellowish brown                                                                           279-281                                                             powder                                            170  H      CH.sub.3                                                                              3-Cl, 4-OH                                                                               Brown powder                                                                              272-273                                ______________________________________                                    

EXAMPLES 171-173

The following compounds were prepared in the same manner as in Referential Example 2 and Example 44.

Compound 171: ##STR66## (m.p.: 140°-142° C.; white powder)

Compound 172: ##STR67## (m.p.: 120°-121° C.; white acicular crystals)

Compound 173: ##STR68## (m.p.: 171°-174° C.; slightly yellow powder)

EXAMPLE 174 ##STR69## N-(n-Phenylpropyl)-N,3,6,6-tetramethyl-5,6-dihydroimidazo[2.1-b]thiazole-2-carboxamide (Compound No. 174)

Suspended in carbon tetrachloride were 2.4 g (0.013 mole) of N-methyl-N-(3-phenylpropyl)acetoacetamide which had been obtained in the same manner as in Referential Example 1, 1.7 g (0.013 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The resultant suspension was heated under reflux for 1 hour. The reaction mixture was then poured in water, followed by extraction with carbon tetrachloride. The carbon tetrachloride solution was washed with water, dried and concentrated to obtain an oily reaction product. The reaction product was purified by chromatography on a silica gel column ("C-300", n-hexane-ethyl acetate), thereby obtaining 1.9 g (0.009 mole) of N-methyl-N-(3-phenylpropyl)-2-chloroacetoacetamide as an oily substance.

Dissolved in 100 ml of methyl ethyl ketone was 1.9 g (0.009 mole) of N-methyl-N-(3-phenylpropyl)-2-chloroacetoacetamide which was obtained above, followed by an addition of 1.2 g (0.009 mole) of 4,4-dimethylimidazolidine-2-thione. The reaction mixture was heated under reflux for 3 hours. After completion of the reaction, methyl ethyl ketone was distilled off and the resulting syrup was dissolved in water. A water-insoluble oil was extracted out with ethyl acetate. The water layer was alkalinized with potassium carbonate, followed by extraction with ethyl acetate. The ethyl acetate solution was dried over anhydrous magnesium sulfate and was then concentrated. The resultant syrup was purified by chromatography on a column (silica gel "C-300", n-hexane/ethyl acetate) to obtain 1.7 g of a light brownish viscous liquid (n_(D) ²⁰ 1.5760).

EXAMPLE 175 ##STR70## N-[2-(3,4-Dichlorophenyl)ethyl]-N,3,6,6-tetramethyl-5,6-dihydroimidazo[2.1-b]thiazole-2-carboxamide hydrochloride (Compound No. 175)

Suspended in carbon tetrachloride were 7.0 g (0.024 mole) of N-methyl-N-(3,4-dichlorophenethyl)acetoacetamide which had been obtained in the same manner as in Referential Example 1, 3.2 g (0.024 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The resultant suspension was heated under reflux for 1 hour. The reaction mixture was then poured in water, followed by extraction with carbon tetrachloride. The carbon tetrachloride solution was washed with water, dried and concentrated to obtain an oily reaction product. The reaction product was purified by chromatography on a silica gel column ("C-300", n-hexane-ethyl acetate), thereby obtaining 5.6 g of N-methyl-N-(3,4-dichlorophenethyl)-2-chloroacetoacetamide as an oily substance.

Dissolved in 150 ml of methyl ethyl ketone was 5.6 g (0.017 mole) of N-methyl-N-(3,4-dichlorophenetyl)-2-chloroacetoacetamide which was obtained above, followed by an addition of 2.2 g (0.017 mole) of 4,4-dimethylimidazolidine-2-thione. The reaction mixture was heated under reflux for 3 hours. After cooling the reaction mixture, n-hexane was added to the reaction mixture, and the resulting syrup was collected and then solidified with ethyl ether. The thus-solidified reaction product was recrystallized from isopropyl alcohol/isopropyl ether to obtain 4.3 g of colorless crystalline powder. m.p. 196°-198° C.

EXAMPLES 176-199

The following compounds were prepared in the same manner as in Referential Example 1 and Examples 174 and 175.

    __________________________________________________________________________      ##STR71##                                                                     Compound                                    Melting point                      No.   R.sub.1                                                                          R.sub.2                                                                          R.sub.3                                                                           R.sub.4                                                                           R.sub.5                                                                             A   X.sub.n                                                                             Appearance    (°C.) or                    __________________________________________________________________________                                                 n.sub.D.sup.20                     176   H H H  H  H    CH.sub.2                                                                           4-F  White powdery crystals                                                                       239-243                            177   H H H  H  H    (CH.sub.2).sub.2                                                                   H    White powder  191-195                            178   H H H  H  H    (CH.sub.2).sub.2                                                                   2,4-Cl.sub.2                                                                        Light yellowish                                                                              229-230                                                          powdery crystals                                 179   H H CH.sub.3                                                                          CH.sub.3                                                                          H    (CH.sub.2).sub.2                                                                   2,4-Cl.sub.2                                                                        Light yellowish                                                                              191-193                                                          powdery crystals                                 180   H H H  H  H    (CH.sub.2).sub.2                                                                   3,4-Cl.sub.2                                                                        Colorless powdery crystals                                                                   222-224                            181   H H CH.sub.3                                                                          CH.sub.3                                                                          H    (CH.sub.2).sub.2                                                                   3,4-Cl.sub.2                                                                        Colorless powdery crystals                                                                   204-205                            182   H H H  H  CH.sub.3                                                                            (CH.sub.2).sub.2                                                                   3,4-Cl.sub.2                                                                        Colorless powdery crystals                                                                   190-191                            183   H H H  H  H    (CH.sub.2).sub.3                                                                   H    Light yellowish                                                                              169-171                                                          powdery crystals                                 184   H H H  H  C.sub.3 H.sub.7i                                                                    CH.sub.2                                                                           3,4-Cl.sub.2                                                                        Milky powdery crystals                                                                       240-242                            __________________________________________________________________________      ##STR72##                                                                     Compound                                    Melting point                      No.   R.sub.1                                                                          R.sub.2                                                                          R.sub.3                                                                           R.sub.4                                                                           R.sub.5                                                                             A   X.sub.n                                                                             Appearance    (°C.) or                    __________________________________________________________________________                                                 n.sub.D.sup.20                     185   H H CH.sub.3                                                                          CH.sub.3                                                                          H    CH.sub.2                                                                           4-F  White powder  122-125                            186   H H CH.sub.3                                                                          CH.sub.3                                                                          H    CH.sub.2                                                                           4-NO.sub.2                                                                          Orange powder 133-139                            187   H H CH.sub.3                                                                          CH.sub.3                                                                          H    CH.sub.2                                                                           4-OCH.sub.3                                                                         White powder  116-122                            188   H H CH.sub.3                                                                          CH.sub.3                                                                          H    (CH.sub.2).sub.3                                                                   H    Fine acicular 135-136                                                          white crystals                                   189   H H H  H  CH.sub.3                                                                            (CH.sub.2).sub.3                                                                   H    Light brownish                                                                               n.sub.D.sup.20 = 1.5940                                          viscous liquid                                   __________________________________________________________________________

Having now fully described the invention, it will be apparent to one of ordinary skill in the art that many changes and modifications can be made thereto without departing from the spirit or scope of the invention as set forth herein. 

We claim:
 1. A 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivative represented by the following general formula [I] ##STR73## wherein R₁, R₂, R₃ and R₄ are either the same or different and mean individually a hydrogen atom or lower alkyl group, Y denotes a group of the following formula: ##STR74## wherein A means a lower alkylene group which may be branched, R₆ denotes a hydrogen atom or a lower alkyl or cycloalkyl group, X denotes a hydrogen or halogen atom or a trifluoromethyl, lower alkyl, lower alkoxy or nitro group, and n stands for an integer of 0-5, and when n is greater than 1, Xs are either the same or different; or a salt thereof.
 2. A 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivative as claimed in claim 1, wherein R₂ means a hydrogen atom and Y denotes a group of the following formula: ##STR75## wherein m stands for an integer of 1-3, and R₆, X and n have the same meaning as defined in claim
 1. 3. A 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivative as claimed in claim 1, wherein R₁, R₂, R₃ and R₄ mean individually a hydrogen atom and Y denotes a group of the following formula: ##STR76## wherein R₁₉ means a hydrogen or alkyl group having 1-3 carbon atoms, m stands for an integer of 1-3, and X and n have the same meaning as defined above.
 4. A 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivative as claimed in claim 1, wherein R₁ and R₂ mean individually a hydrogen atom, R₃ and R₄ denote individually a methyl group, and Y is a group of the following formula: ##STR77## wherein R₁₉ means a hydrogen atom or alkyl group having 1-3 carbon atoms, m stands for an integer of 1-3, and X and n have the same meaning as defined above.
 5. A 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivative as claimed in claim 1, wherein R₁ and R₃ mean individually a methyl group, R₂ and R₄ denote individually a hydrogen atom, and Y is a group of the following formula: ##STR78## wherein R₁₉ means a hydrogen atom or alkyl group having 1-3 carbon atoms, m stands for an integer of 1-3, and X and n have the same meaning as defined above.
 6. N-(3,4-Dichlorobenzyl)-N,3-dimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide or a salt thereof.
 7. N-(4-Trifluoromethylbenzyl)-N,3,6,6-tetramethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide or a salt thereof.
 8. N-[2-(4-Chlorophenyl)ethyl]-N,3-dimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide or a salt thereof.
 9. N-(2-Phenylethyl)-N,3,6,6-tetramethyl-5,6-dihydroimidazo[2,1-b]thiazole-2'-carboxamide or a salt thereof.
 10. N-[2-(4-Chlorophenyl)ethyl]-N,3,6,6-tetramethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide or a salt thereof.
 11. N-Benzyl-N,3,6,6-tetramethyl-5,6-dihydroimidazo[2,1-b]-thiazole-2-carboxamide or a salt thereof.
 12. N-(2-Phenylethyl)-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide or a salt thereof. 